fig2

Figure 2. Molecular mechanisms of ferroptosis. Ferroptosis is an iron-dependent cell death characterized by increased lipid peroxidation. Ferroptosis involves an imbalance in the lipid peroxidation and antioxidant systems. IREB2, TFRC, and NCOA4-mediated ferritinophagy promote ferroptosis by increasing Fe²⁺ in cells, whereas ferroportin-mediated iron export inhibits ferroptosis. Subsequently, Fe²⁺ generates ROS through Fenton reaction. Furthermore, ACSL4, LPCAT3, LOXs, and POR pathways facilitate the peroxidation of PUFA, which is required for oxidative damage in ferroptosis. Meanwhile, PKCβII and PCK2 promote the phosphorylation of ACSL4, leading to enhanced phospholipid remodeling capability of ACSL4. Several antioxidant defense systems such as the SLC7A11-GSH-GPX4 and FSP1/DHODH-CoQ pathways play crucial roles in counteracting lipid peroxidation. Moreover, SCD and LPCAT1 inhibit ferroptosis by promoting MUFA or SFA-phospholipids synthesis. SFA: Saturated fatty acids; PE: phosphatidylethanolamine; SLC7A11: solute carrier family 7 member 11; TFRC: transferrin receptor; FSP1: ferroptosis suppressor protein-1; CKB: creatine kinase B; IREB2: iron-responsive element binding protein 2; DHODH: dihydroorotate dehydrogenase; GSH: glutathione; GPX4: glutathione peroxidase 4; ROS: reactive oxygen species; MUFA: monounsaturated fatty acid; PCK2: phosphoenolpyruvate carboxykinase 2; PKCβII: protein kinase CβII; ACSL4: acyl-CoA synthetase long-chain family member 4; POR: P450 oxidoreductase; LOXs: lipoxygenases; SCD: stearoyl-CoA desaturase; LPCAT3: lysophosphatidylcholine acyltransferase 3; LPCAT1: lysophosphatidylcholine acyltransferase 1; CoA: coenzyme A; CoQH2: dihydrouquinone; CoQ: ubiquinone.